Formylpeptide receptors (FPR) play an important role in helping polymorphonuclear leukocytes (PMN) locate and neutralize bacterial infections. Defects in FPR expression and PMN chemotaxis are common in patients with aggressive periodontitis (AP), a disorder that produces severe, rapid periodontal destruction. AP is most prevalent in African-Americans and exhibits a familial aggregation. Our studies show that AP is associated with the silent single nucleotide polymorphism (SNP) c.348T>C in the gene that encodes FPR. In African-Americans, the 348T allele occurs at a higher frequency in individuals with AP than in healthy controls (P = 0.001). We hypothesize that 348T is linked to one or more SNPs in the FPR gene promoter, which could contribute to impaired FPR expression and increased risk of developing AP. An analogous linkage of silent coding SNPs with promoter SNPs exists in the beta2-adrenergic receptor gene. This project will explore the relationship between FPR SNPs, FPR expression defects, chemotaxis defects and susceptibility to AP in African-Americans. In Specific Aim 1, an FPR gene fragment will be cloned and sequenced to characterize: a) the association of c.348T>C (and other individual and linked SNPs in the FPR coding region) with AP, and b) the association of c.348T>C with SNPs in the FPR promoter region. In Specific Aim 2, the relationship of c.348T>C to defects in PMN chemotaxis and FPR expression will be characterized. If these studies confirm our hypothesis, they will lay the foundation for studies that will explain at the molecular level why c.348T>C is associated with defective FPR expression and justify a larger clinical study to develop methods to detect individuals susceptible to AP. If a valid indicator of susceptibility were available, it would be prudent to test young African-Americans who are at increased risk of developing AP for the presence of pathogens. Targeted therapeutic intervention to eliminate pathogens prior to clinical expression of AP could mitigate periodontal destruction, minimize functional and esthetic problems related to tooth loss, and reduce the cost of dental care. [unreadable] [unreadable] [unreadable]